Project Summary Despite more than one in five children in South Africa being HIV exposed uninfected (HEU), there are no systems in South Africa to evaluate in a sustainable long-term manner the outcomes of children exposed to HIV and antiretroviral drugs in utero. Through rigorous observational epidemiologic and modern biostatistical methods, the CHERISH study (Children HIV Exposed Uninfected Research to Inform Survival and Health) presents an opportunity to determine whether at a population and individual level survival, hospitalization, growth and neurodevelopmental outcomes are equivalent in children who are HEU and children who are HIV unexposed uninfected (HUU) in the era of universal maternal antiretroviral therapy. In the Western Cape Province of South Africa, where maternal antenatal HIV prevalence is 19%, the Western Cape Provincial Health Data Center curates electronic individual-linked health data from multiple sources according to unique patient identifiers with routine birth linkage of maternal and infant unique identifiers. We will leverage this resource and build on existing NIH investments in the Western Cape to establish a Western Cape province- wide cohort of births from 2018-2024 (R61 360,000; R33 585,000), in synchrony with two sentinel-sites (R61 36,000; R33 58,500), a static detailed cohort (R61 & R33 450) and dynamic light-touch cohort (R61 450; R33 1,800). Specifically we propose during the R61 to establish and optimize sustainable measurement of key in utero and postnatal exposures and outcomes in children who are HEU and HUU in the Western Cape at 4 levels: province-wide population cohort; urban and rural sentinel sites (supported by NIH funding until 2020, to be expanded through CHERISH); static detailed urban cohort (NICHD-funded B-Positive cohort, follow-up to be extended through CHERISH); dynamic light-touch urban and rural cohorts (to be newly established by CHERISH). During the R33 we will harness these cohorts to pursue three scientific aims: to compare 1) infant and under 3-year survival, 2) infant and under 3-year all-cause and infectious-cause hospitalization and 3) growth and neurodevelopmental outcomes at age 3-5 years in children who are HEU and HUU; Furthermore, for each aim we will identify factors amenable to intervention that mediate the effects of HIV and ARV exposure on survival, hospitalization, growth and neurodevelopment. The province-wide cohort will inform the population-level impact of HIV/ARV-exposure on child survival and morbidity in children who are HEU compared to HUU with similar socioeconomic, nutritional and environmental constraints to health in an HIV high-prevalence setting. The sentinel-site, static and dynamic cohorts will apply advanced statistical methods to identify causal pathways and sub-groups of children who are HEU with survival and morbidity disparities to inform design of targeted interventions feasible for health systems in HIV high prevalence settings. This presents a sustainable, innovative and adequately sized cohort model that with modest ongoing investment can continue to accumulate mother-child pairs with lifelong follow-up and opportunities to evaluate changes in in utero exposure to HIV and its prevention and treatment modalities as the epidemic evolves.